1,4-Dihydropyridines are known to treat hypertension and are classified mainly as calcium channel blockers. First synthetic process for 1,4-dihydropyridines was reported by Arthur Hantzsch (Justus Liebigs Ann. Chem., 1882, 215, 1) In general commercial manufacturing of 1,4-dihydropyridines involves reaction of an aromatic aldehyde, an amine/ammonia and β-keto ester derivatives.
Several pharmaceutically acceptable 1,4-dihydropyridine-3,4-dicarboxylic acid derivatives are known in the literature such as nicardipine, felodipine, nifedipine, nimodipine, nisoldipine, etc., Substituents at 3 and 5 position of 1,4-dihydropyridines categorizes these molecules either symmetrical or unsymmetrical. Symmetrical 1,4-dihydropyridines are relatively easy to synthesis with much purity and yield.
Four different synthetic approaches are known in the art to synthesis unsymmetric 1,4-dihydropyridines The first procedure involves preparation of the benzylidene derivative from the aromatic aldehyde and the amino crotonate. The benzylidene derivative is further reacted with β-keto ester to yield the 1,4-dihydropyridines. (Scheme-1). In Example 7 of German patent 2407115 (U.S. Pat. No. 3,985,758) there is described a for obtaining nicardipine in an overall yield of approximately 12% by reacting the intermediate chloroethyl methyl 2,6-dimethyl-4-(m-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate with N-methyl benzyl amine.

The second procedure (Scheme-2) involves preparation of benzylidene derivatives from the aromatic aldehyde and the β-keto ester; in some reports a catalyst was used at this stage, and then the benzylidene derivative is reacted with amino crotonate to produce the 1,4-dihydropyridines. The yield achieved when using this procedure has been problematic. Specifically, the generally poor overall yield of nicardipine using this procedure is due to a lack of purity in the intermediates, such as 2-(N-benzyl-N-methylamino)-ethyl acetoacetate, which is obtained at a very poor yield of 10.5% by reacting 2-(N-benzyl-N-methylamino)-ethanol with ethyl acetoacetate in an anhydrous medium (M. Iwanami et al., Chem. Pharm. Bull. 27(6), 1426-1440 (1979)). Examples in the art using this procedure are given for 1,4-dihydropyridine derivatives in U.S. Pat. No. 3,932,645 and U.S. Pat. No. 6,689,799, for Amlodipine in U.S. Pat. No. 6,784,297, and for nicardipine hydrochloride in JP 8217749.

U.S. Pat. No. 3,932,645 reports a process of making 1,4dihydropyridines by condensing an aldehyde with an acetoacetate to yield a benzylidene intermediate, and further reaction with amino crotonates or acetoacetate and amine/ammonia. As referred to in U.S. Pat. No. 6,858,747, when acid is used as a catalyst in the preparation of the benzylidene derivative, a mixture of aldol by-products are observed; this is also reported in U.S. Pat. No. 5,310,917, and similar examples are reported in U.S. Pat. No. 5,977,369 and U.S. Pat. No. 4,600,778. U.S. Pat. No. 6,649,767 discloses one pot, two stage reactions catalyzed by magnesium (II) base at the benzylidene stage and by an acid at the condensation stage.
The third procedure involves conversion of symmetric 1,4-dihydropyridine by selectively replacing one of the ester moieties by a desired substitution (Scheme-3). This approach also has a poor yield and a high level of impurities in downstream products. It is known that N-aryl- or N-alkyl-substituted dihydropyridine-3,5-dicarboxylates are easily hydrolyzed under the action of alkalis to the corresponding dihydropyridine-monocarboxylic acids (A. Sausins et al., Khim. Geterocikl. Soedin., 2, 272 (1978)). Contrary to the easy alkaline hydrolysis of N-aryl- and N-alkyl-substituted dihydropyridine-3,5-dicarboxylates, the N-unsubstituted dihydropyridine-3,5-dicarboxylates are not, or are only to a small extent, hydrolyzed to the corresponding monoesters of dicarboxylic acids (N. Eisner et al., Chem. Rev. 72, 1, 4 (1972) or B. Loev et al., J. Heterocyclic Chem. 12, 363 (1975); M. Iwanami et al., Chem. Pharm. Bull. 27(6), 1426-1440 (1979), and T. Shibanuma, Chem. Pharm. Bull., 28(9) 2809-2812 (1980), JP 03017059, U.S. Pat. No. 4,818,855.) U.S. Pat. No. 4,769,465 describes a process of preparing nicardipine hydrochloride in overall yield amounts to 46% with respect to the starting materials.

The fourth procedure (Scheme-4) is the preparation of unsymmetric 1,4-dihydropyridines by a one pot synthesis using an aldehyde, β-ketoester, and aminocrotonate or mixture of acetoacetate and an amine/amine salt. Even though the synthetic methodologies used for symmetrical 1,4-dihydropyridines could be used to synthesize unsymmetrical 1,4-dihydropyridines, the same yield and purity are not met and so the processes are not commercially successful. In EP0445987 and JP55860/90, single pot preparation of nicardipine hydrochloride (160 g, yield 25.8% by mole ratio) has been reported.

General drawbacks with the reported synthetic processes of 1,4-dihydropyridines are poor yield and low purity. Most of the single pot syntheses of unsymmetrical 1,4-dihydropyridines provide a maximum yield of about 20% by mol with respect to the β-ketoester. The low yield is especially true in the case of nicardipine hydrochloride, which is poorly soluble in water, hence making it difficult to remove the impurities which are very similar in chromatographic characteristics of nicardipine hydrochloride.
Most of the 1,4-Dihydropyridine hydrochloride salts (especially nicardipine hydrochloride and nifedipine hydrochloride) are very poorly soluble in water. Methods for enhancing the solubility to produce a stable aqueous solution of 1,4-dihydropyridines are known in the art. The solubility of nicardipine hydrochloride is typically enhanced through the use of organic acids, such as citric acid, acetic acid, and the like. However, the use of mineral acids, especially hydrochloric acid, reduces the solubility of nicardipine hydrochloride at a pH in the range of 3 to 4, likely by the common ion effect. Thus, preparing a stable, parenteral, aqueous solution of nicardipine hydrochloride is of keen pharmaceutical interest.
Preparation of aqueous solution of nicardipine hydrochloride in presence of a polyhydric alcohol such as sorbitol, mannitol, xylitol etc., in a pH range of about 2.5 to 5.5 has been disclosed by Katayasu et al. (JP 102991/84, EP 0162705, U.S. Pat. No. 4,880,823, and U.S. RE34618). The data reported in EP0162705 reveals that the nicardipine hydrochloride in aqueous solution so produced is unstable and about 30% to about 50% of the potency is lost during storage. Preparation of a nicardipine parenteral solution has been reported by Calum et al. (U.S. Pat. No. 5,164,405) using a pharmaceutically acceptable buffer at a pH of about 3 to 4.5; the buffers described include citrate, acetate, phosphate, and lactate in presence of polyhydric alcohols such as mannitol, sorbitol, dextrose, glucose, polyethylene glycol, and glycerol.
Parenteral solutions of nicardipine are reported with added buffers (JP2000072673 and JP2003137782), with added phosphoric acid (JP 20033104889), with added calcium or sodium gluconate as stabilizer (JP2001316266), and with the addition of 2-HP-beta-cyclodextrin for the manufacture of a powder for making an injectable (CN1326731). Japanese patent JP 11193234 discloses parenteral solutions of nicardipine hydrochloride in which an acid is present; such acids include hydrochloride acid, phosphoric acid, tartaric acid, lactic acid, citric acid, amino acetic acid, glutamic acid, and alanine. None of the examples in this JP publication are specific to the use L-arginine; nevertheless the claims recite arginine, aspartic acid, and cysteine as examples of amino acids that can be used as the acid. Also in this JP publication, the ratio of the added amino acid to the nicardipine hydrochloride is about 1 to 50 times by weight. At this concentration of nicardipine hydrochloride to amino acid (1:1 to 50:1), the solubility of nicardipine hydrochloride will be very poor at room temperature; it would require heating to at least about 50° to 60° C. to dissolve the nicardipine HCl and obtain a clear solution. Such heat-assisted dissolution leads to degradation of nicardipine, giving several impurities, some of which might be toxic. It also has been reported in JP 1193234 that the parenteral solution of nicardipine hydrochloride prepared by using amino acids is not stable, that a significant drop in the nicardipine content of the parental solution (up to about 9.7%) is observed after only 21 days. This relatively poor storage stability is possibly due to thermal degradation of nicardipine, a reaction catalyzed by the excess concentration of amino acids present. It should be apparent that the use of an organic acid buffer in an aqueous solution with the intent to enhance the solubility of nicardipine hydrochloride in water would have stability concerns because the organic acid would likely participate in catalytic hydrolysis of the ester groups present on the nicardipine molecule. The nicardipine parenteral injectables marketed as Cardene brand solutions generally have degradation impurities at a level of more than 0.5%. The hydrolytic degradation products of nicardipine are shown in Scheme-6 below:

In general, the prior one pot, single step syntheses of 1,4-dihydropyridines unsymmetrically substituted at the 3 and 5 positions used an equimolar ratio of the aldehyde, aminocrotonate and the β-keto ester. The prior processes lead to a significant yield of the symmetrical 3,5-substituted compounds, thereby reducing the yield and purity of the required 1,4-dihydropyridines. All the prior art manufacturing processes for nicardipine involve using one mole equivalent of aldehyde with regard to the β-keto ester and the amino crotonate. The overall yield with respect to β-keto ester is about 16 to 20% by mole.